Abstract In the context of heart transplantation (Tx), which is the focus of this application, primary graft failure and cardiac allograft vasculopathy (AV) remain the major limitations to short and long-term survival. The course, severity and onset of AV have changed little since the inception of cardiac Tx surgery, despite improvements in T cell immunosuppression. The precise mechanisms involved in the development of primary graft failure and chronic AV are not well understood, here we investigate the role of donor brain death (BD)-induced injury and ischemia reperfusion injury (IRI) in the development of AV, and the role of complement in these processes. Brain death-induced injury and IRI are unavoidable events in most organ transplantations, and they are major clinical problems that are thought to play important roles in both short-term and long-term graft survival. Natural self-reactive IgM and complement play a major role in both types of injury, and here we investigate novel approaches of using graft-targeted IgM blockade and complement inhibition, administered as an acute immunosuppressant after cardiac transplantation, to determine how acute post-transplant inflammation and injury modulates the development of AV (chronic rejection). We will also investigate how complement and graft-targeted strategies of IgM and complement inhibition affect the development of cardiac AV in the context of subtherapeutic T cell immunosuppressive therapy (rapamycin and tacrolimus), and how the use of complement inhibition as an adjuvant therapy modulates AV. By linking moieties that target injury-specific post- ischemic neoepitopes expressed in cardiac (and other organ/tissue) grafts to different complement inhibitors, we will be able to investigate how complement modulates acute injury and subsequent chronic rejection. We expect to elucidate complement-dependent mechanisms involved in the development of AV, and to identify a therapeutic candidate for further development that will permit the use of immune-sparing immunosuppressive therapies.